Immune Implications of Cholesterol-Containing Lipid Nanoparticles.

The majority of clinically approved nanoparticle-mediated therapeutics are lipid nanoparticles (LNPs), and most of these LNPs are liposomes containing cholesterol. LNP formulations significantly alter the drug pharmacokinetics (PK) due to the propensity of nanoparticles for uptake by macrophages. In addition to readily engulfing LNPs, the high expression of cholesterol hydroxylases and reactive oxygen species (ROS) in macrophages suggests that they will readily produce oxysterols from LNP-associated cholesterol. Oxysterols are a heterogeneous group of cholesterol oxidation products that have potent immune modulatory effects. Oxysterols are implicated in the pathogenesis of atherosclerosis and certain malignancies; they have also been found in commercial liposome preparations. Yet, the in vivo metabolic fate of LNP-associated cholesterol remains unclear. We review herein the mechanisms of cellular uptake, trafficking, metabolism, and immune modulation of endogenous nanometer-sized cholesterol particles (i.e., lipoproteins) that are also relevant for cholesterol-containing nanoparticles. We believe that it would be imperative to better understand the in vivo metabolic fate of LNP-associated cholesterol and the immune implications for LNP-therapeutics. We highlight critical knowledge gaps that we believe need to be addressed in order to develop safer and more efficacious lipid nanoparticle delivery systems.

Development of a TDCR counting system with anti-coincidence detectors.

When employing the TDCR method for standardization of low-activity liquid scintillation samples, fluctuations in system background can significantly impact both measurement uncertainties and minimum detectable activity (MDA). To mitigate this impact, a TDCR counting system with anti-coincidence detectors was developed. By analyzing the time difference distribution spectrum between the anti-coincidence channel and ß channel, optimal parameters for the anti-coincidence module are determined. The objective of the study is to enhance the effectiveness of the anti-coincidence technique while minimizing the removal of real events. Finally, two sets of 3H and 14C samples with known activities of around 1 Bq are prepared via dilution to validate the performance of the system. Compared to without anti-coincidence, the background has been reduced by nearly 84%, leading to decreased fluctuations in the activity results.

Discovery of D8-03 as an Inhibitor of Intracellular Growth of Francisella tularensis.

Francisella tularensis is a Gram-negative facultative intracellular bacterial pathogen that is classified by the Centers for Disease Control and Prevention as a Tier 1 Select Agent. F. tularensis infection causes the disease tularemia, also known as rabbit fever. Treatment of tularemia is limited to few effective antibiotics which are associated with high relapse rates, toxicity, and potential emergence of antibiotic-resistant strains. Consequently, new therapeutic options for tularemia are needed. Through screening a focused chemical library and subsequent structure-activity relationship studies, we have discovered a new and potent inhibitor of intracellular growth of Francisella tularensis, D8-03. Importantly, D8-03 effectively reduces bacterial burden in mice infected with F. tularensis. Preliminary mechanistic investigations suggest that D8-03 works through a potentially novel host-dependent mechanism and serves as a promising lead compound for further development.

The host mannose-6-phosphate pathway and viral infection.

Viruses, despite their simple structural composition, engage in intricate and complex interactions with their hosts due to their parasitic nature. A notable demonstration of viral behavior lies in their exploitation of lysosomes, specialized organelles responsible for the breakdown of biomolecules and clearance of foreign substances, to bolster their own replication. The man-nose-6-phosphate (M6P) pathway, crucial for facilitating the proper transport of hydrolases into lysosomes and promoting lysosome maturation, is frequently exploited for viral manipulation in support of replication. Recently, the discovery of lysosomal enzyme trafficking factor (LYSET) as a pivotal regulator within the lysosomal M6P pathway has introduced a fresh perspective on the intricate interplay between viral entry and host factors. This groundbreaking revelation illuminates unexplored dimensions of these interactions. In this review, we endeavor to provide a thorough overview of the M6P pathway and its intricate interplay with viral factors during infection. By consolidating the current understanding in this field, our objective is to establish a valuable reference for the development of antiviral drugs that selectively target the M6P pathway.

High-Performance Ultraviolet Organic Light-Emitting Diodes Enabled by Double Boron-Oxygen-Embedded Benzo[m]tetraphene Emitters.

Ultraviolet organic light-emitting diodes (UV OLEDs) have attracted increasing attention because of their promising applications in healthcare, industry, and agriculture; however, their development has been hindered by the shortage of robust UV emitters. Herein, we embedded double boron-oxygen units into nonlinear polycyclic aromatic hydrocarbons (BO-PAHs) to regulate their molecular configurations and excited-state properties, enabling novel bent BO-biphenyl (BO-bPh) and helical BO-naphthyl (BO-Nap) emitters with hybridized local and charge-transfer (HLCT) characteristics. They could be facilely synthesized in gram-scale amounts via a highly efficient two-step route. BO-bPh and BO-Nap showed strong UV and violet-blue photoluminescence in toluene with full width at half-maximum values of 25 and 37 nm, along with quantum efficiencies of 98 and 99%, respectively. A BO-bPh-based OLED showed high color purity UV electroluminescence peaking at 394 nm with Commission Internationale de l'Eclairage (CIE) coordinates of (0.166, 0.021). Moreover, the device demonstrated a record-high maximum external quantum efficiency (EQE) of 11.3%, achieved by successful hot exciton utilization. This work demonstrates the promising potential of double BO-PAHs as robust emitters for future UV OLEDs.

Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease.

Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2M28L, that confers an increased AD risk. PLCG2P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbated the plaque burden associated with altered phagocytosis and Aß clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.

Effect of N-Aryl Para-Benzhydryl Substituent on the Thermal Stability of α-Diimine Nickel Catalyst.

The thermal stability of α-diimine nickel catalysts has always been the focus of research. The introduction of large groups in the backbone or N-aryl ortho-position is a relatively mature solution. However, the question of whether the N-aryl bond rotation is a factor affecting the thermal stability of nickel catalysts is still open. In this work, the effects of N-aryl para-benzhydryl substitutes on catalyst thermal stability are investigated, and the results of ethylene polymerization and the factors affecting thermal stability (steric effect, electronic effect, five-membered coordination ring stability, N-aryl bond rotation, etc.) are systematically analyzed. It is believed that the introduction of large steric hindrance groups at the N-aryl para-position hinders the rotation of the N-aryl bond. This obstacle effect is beneficial to improving catalyst thermal stability, and the obstacle capacity is weakened with the increase of ortho-substituent size.

The differences between broad bean koji fermented in laboratory and factory conditions by an efficient Aspergillus oryzae.

Broad bean paste-meju was fermented by a mixture of broad bean koji and saline; koji fermentation is an essential process for the production of broad bean paste-meju. Aspergillus oryzae was the most widely used in sauce fermentation. The purpose of this study was to research the factory adaptability of the highly efficient A. oryzae PNM003 and further evaluate the effect of fermentation conditions and fermentation strains on koji. A. oryzae PNM003 was compared with the widely used strain HN 3.042 not only in the laboratory but also in factory conditions (large scale). Results showed that the koji made with the same starter in the factory had a greater amount of fungi than that in the laboratory. Bacteria and yeast levels in HN_L koji were higher than in PN_L koji. As for fungi constitution, almost only Aspergillus survived in the end through the microorganism self-purification process during koji fermentation. As for the bacterial constitution, koji was grouped by fermentation conditions instead of fermentation starter. PN koji had higher protease activity and a higher content of total acids, amino acid nitrogen, amino acids, and organic acids in the laboratory conditions. Nevertheless, in factory conditions, PN koji and HN koji had similar indexes. As for volatile flavor compounds, koji made with the two starters in the same condition was grouped together. As for the same starter, there were more flavor compounds metabolized in the factory condition than in the laboratory condition, especially esters and alcohols. The results showed PN was a highly efficient strain to ferment koji, but the advantages were expressed more remarkably in laboratory conditions. In brief, the fermented condition had a greater influence than the fermentation starter for broad bean koji.

Flexible integrated sensor with asymmetric structure for simultaneously 3D tactile and thermal sensing.

The human body detects tactile stimuli through a combination of pressure force and temperature signals via various cutaneous receptors. The development of a multifunctional artificial tactile perception system has potential benefits for future robotic technologies, human-machine interfaces, artificial intelligence, and health monitoring devices. However, constructing systems beyond simple pressure sensing capabilities remains challenging. Here, we propose an artificial flexible and ultra-thin (50 µ m) skin system to simultaneously capture 3D tactile and thermal signals, which mimics the human tactile recognition process using customized sensor pairs and compact peripheral signal-converting circuits. The 3D tactile sensors have a flower-like asymmetric structure with 5-ports and 4 capacitive elements in pairs. Differential and average signals would reveal the curl and amplitude values of the fore field with a resolution of 0.18/mm. The resistive thermal sensors are fabricated with serpentine lines and possess stable heat-sensing performance (165 mV/°C) under shape deformation conditions. Real-time monitoring of the skin stimuli is displayed on the user interface and stored on mobile clients. This work offers broad capabilities relevant to practical applications ranging from assistant prosthetics to artificial electronic skins.

Observation and research of deep underground multi-physical fields-Huainan -848 m deep experiment.

Compared with the surface, the deep environment has the advantages of allowing "super-quiet and ultra-clean"-geophysical field observation with low vibration noise and little electromagnetic interference, which are conducive to therealization of long-term and high-precision observation of multi-physical fields, thus enabling the solution of a series of geoscience problems. In the Panyidong Coal Mine, where there are extensive underground tunnels at the depth of 848 m belowsea level, we carried out the first deep-underground geophysical observations, including radioactivity, gravity, magnetic, magne-totelluric, background vibration and six-component seismic observations. We concluded from these measurements that (1) the background of deep subsurface gravity noise in the long-period frequency band less than 2 Hz is nearly two orders ofmagnitude weaker than that in the surface observation environment; (2) the underground electric field is obviously weaker thanthe surface electric field, and the relatively high frequency of the underground field, greater than 1 Hz, is more than two orders of magnitude weaker than that of the surface electric field; the east-west magnetic field underground is approximately the same asthat at the surface; the relatively high-frequency north-south magnetic field underground, below 10 Hz, is at least one order ofmagnitude lower than that at the surface, showing that the underground has a clean electromagnetic environment; (3) in additionto the high-frequency and single-frequency noises introduced by underground human activities, the deep underground spacehas a sig-nificantly lower background vibration noise than the surface, which is very beneficial to the detection of weakearthquake and gravity signals; and (4) the underground roadway support system built with ferromagnetic material interferesthe geomagnetic field. We also found that for deep observation in the "ultra-quiet and ultra-clean" environment, the existinggeophysical equipment and observation technology have problems of poor adaptability and insufficient precision as well asdata cleaning problems, such as the effective separation of the signal and noise of deep observation data. It is also urgent tointerpret and comprehensively utilize these high-precision multi-physics observation data. Electronic Supplementary Material: Supplementary material is available in the online version of this article at 10.1007/s11430-022-9998-2.

Analysis of and Reduction in Noise in Current Measurement of XCP under the Laboratory Condition.

Expendable current profiler (XCP) is one of the most vital devices detecting ocean currents. Compared with other methods, the expendable feature makes trials with XCP much faster and more hidden, while the accuracy of XCP is considerably influenced by electromagnetic noise all around. Aiming at researching the influence and reducing the noise, this study carried out laboratory simulation experiments. The designed laboratory experiments mainly have a self-developed rotation gear, an XCP prototype, a plastic flume, and two copper plates as power. Firstly, these experiments analyzed the main sources of electromagnetic noise for XCP detection. Secondly, we built a noise simulation environment and conducted XCP detection experiments under different noise in the flume. The data obtained by XCP were transmitted to the computer to be stored and processed. The results show the internal noise impact on XCP is significantly less than the external. For an excitation power of 1 mV, the offset of theoretical and actual data brought by internal noise is 12 times smaller than external and can be corrected.

A Low-Voltage and Power-Efficient Capless LDO Based on the Biaxially Driven Power Transistor Technique for Respiration Monitoring System.

In this study, a 0.8-V- Vin 200-mA- Io capless low-dropout voltage regulator (LDO) is developed for a wireless respiration monitoring system. The biaxially driven power transistor (BDP) technique is proposed in the LDO, with a current driven stimulation on the bulk and a voltage on the gate terminal. With the BDP technique, an adaptively biased current-driven loop (ABCL) is designed which can reduce the high threshold voltage of power transistor, thus presenting lower input voltage and reduced power consumption. Moreover, this loop can provide an improved dynamic response due to its increased discharging current. Based on an error amplifier with enhanced DC gain and gain bandwidth, the capless LDO achieves superior power supply rejection (PSR) and stability without a complex frequency compensation mechanism. The proposed LDO is fabricated in the SMIC 180 nm process with a chip area of 0.046 mm 2. Measurement results indicate that this LDO can obtain a 200-mA load current range and greater than -66 dB PSR up to 1 kHz at a supply voltage as low as 0.8 V.

Clip-assisted endoloop ligation of the mucosal defect after resection of colorectal polyps decreased postprocedural delayed bleeding.

Background: Postprocedural delayed bleeding (PDB) remains the most common major complication of colorectal polypectomy. Incomplete clip closure of mucosal defect and unclosed injured blood vessels in gaps between clips may be the risk factors for PDB. Objectives: To observe whether completely no-gap closure of mucosal defect after polypectomy can reduce PDB occurrence. Design: Single-center, retrospective case-control study. Methods: In this study based on historical comparisons of patients in 2 time periods, only the patients with polyps sized between 6 and 15 mm were included. A new clip-assisted endoloop ligation (CAEL, treatment group) method was used between January 2019 and December 2020, and a traditional simple clip closure (SCC, control) was used Between January 2017 and December 2018 to prevent PDB after polypectomy. The rate of PDB of two groups and risk factors for PDB were evaluated. Results: Totally 4560 patients were included in the study; 2418 patients belong to CAEL group, and 2142 patients belong to SCC group. The overall rate of PDB was significantly lower in CAEL group compared to SCC group (0.6% versus 1.5%, p < 0.00). On multivariate logistic analysis, CAEL was a significant independent preventive factor for PDB (odds ratio (OR), 0.092; 95% confidence interval (CI), 0.029-0.3335; p = 0.000). Polyps located at rectum (colon versus rectum) represented a significant independent risk factor for PDB (OR, 11.888; 95% CI, 3.343-42.269; p = 0.001). Conclusion: Completely no-gap closure of mucosal defect after polypectomy further reduced the rate of PDB for polyps sized between 6 and 15 mm. CAEL may be a significant independent preventive factor for PDB. Polyps located at the rectum may be a significant independent risk factor for PDB.

Toward a BT.2020 green emitter through a combined multiple resonance effect and multi-lock strategy.

Color-saturated green-emitting molecules with high Commission Internationale de L'Eclairage (CIE) y values have great potential applications for displays and imaging. Here, we linked the outer phenyl groups in multiple-resonance (MR)-type blue-emitting B (boron)-N (nitrogen) molecules through bonding and spiro-carbon bridges, resulting in rigid green emitters with thermally activated delayed fluorescence. The MR effect and multiple interlocking strategy greatly suppressed the high-frequency vibrations in the molecules, which emit green light with a full-width at half-maximum of 14 nm and a CIE y value of 0.77 in cyclohexane. These were the purest green molecules with quantum efficiency and color purity that were comparable with current best quantum dots. Doping these emitters into a traditional green-emitting phosphorescence organic light-emitting diode (OLED) endowed the device with a Broadcast Service Television 2020 color-gamut, 50% improved external quantum efficiency, and an extremely high luminescence of 5.1 × 105 cd/m2, making it the greenest and brightest OLED ever reported.

Dynamics of allosteric regulation of the phospholipase C-γ isozymes upon recruitment to membranes.

Numerous receptor tyrosine kinases and immune receptors activate phospholipase C-γ (PLC-γ) isozymes at membranes to control diverse cellular processes including phagocytosis, migration, proliferation, and differentiation. The molecular details of this process are not well understood. Using hydrogen-deuterium exchange mass spectrometry, we show that PLC-γ1 is relatively inert to lipid vesicles that contain its substrate, phosphatidylinositol 4,5-bisphosphate (PIP2), unless first bound to the kinase domain of the fibroblast growth factor receptor (FGFR1). Exchange occurs throughout PLC-γ1 and is exaggerated in PLC-γ1 containing an oncogenic substitution (D1165H) that allosterically activates the lipase. These data support a model whereby initial complex formation shifts the conformational equilibrium of PLC-γ1 to favor activation. This receptor-induced priming of PLC-γ1 also explains the capacity of a kinase-inactive fragment of FGFR1 to modestly enhance the lipase activity of PLC-γ1 operating on lipid vesicles but not a soluble analog of PIP2 and highlights potential cooperativity between receptor engagement and membrane proximity. Priming is expected to be greatly enhanced for receptors embedded in membranes and nearly universal for the myriad of receptors and co-receptors that bind the PLC-γ isozymes.

Study of bacterial community succession and reconstruction of the core lactic acid bacteria to enhance the flavor of paocai.

Paocai is a widely consumed traditional Chinese fermented vegetable product. To study the effects of bacterial community succession and core microbial reconstruction on the flavor of paocai, culture-dependent and culture-independent methods were used to analyze the bacterial community structure of naturally fermented paocai. HPLC and GC-MS were used to investigate changes in flavor compounds during the fermentation of paocai. Key odorants were identified by olfactometry combined with GC-MS. The results showed that dominant bacteria in the paocai fermentation were mostly cultivable. Leuconostoc mesenteroides, Weissella cibaria, and Lactococcus lactis appeared at the start of fermentation, Leu. mesenteroides, L. lactis, Lactiplantibacillus plantarum, and Levilactobacillus brevis appeared in the middle of fermentation, and L. plantarum dominated fermentation in the late stage. Leuconostoc mesenteroides CPTCC 1R3 (LEM), Weissella cibaria CPTCC 1R15 (WC), Levilactobacillus brevis CPTCC 3R8 (LB), and Lactiplantibacillus plantarum CPTCC 5R10 (LP) were screened from naturally fermented paocai and used for microbial reconstruction, revealing that the growth and fermentation profiles of the strains were closely related to the evolution of the bacterial community. Paocai inoculated with LEM had the following characteristics: fast fermentation, quickly disappearance of pungent odor of the raw materials, and the improved flavor and taste. Paocai inoculated with WC and LB contained ethanol and mannitol, but inoculated strains were poorly acid-tolerated. However, they can be used as auxiliary strains to enhance the flavor of paocai. Sample inoculated with LP resulted in slow fermentation and massive acid production. Mixed culture fermentation of paocai has more advantages than pure culture fermentation. Leu. mesenteroides and L. plantarum were the core microorganisms related to the flavor formation of paocai. These findings contributed to the better understanding of mechanisms underlie in the microbial community succession and flavor formation during paocai fermentation.

Zero-Zero Energy-Dominated Degradation in Blue Organic Light-Emitting Diodes Employing Thermally Activated Delayed Fluorescence.

Blue-emitting organic light-emitting diodes (OLEDs) fall significantly behind other OLEDs in operational stability. To better understand the key factors governing the stability of blue OLEDs employing thermally activated delayed fluorescence (TADF), nine efficient sky-blue to green TADF emitters with different frontier orbital energy levels and different TADF lifetimes have been designed and synthesized on the basis of charge-transfer (CT) acridine/phenyltriazine derivatives. Among them, ToDMAC-TRZ, a molecule composed of a 9,9-dimethyl-2,7-di-o-tolyl-9,10-dihydroacridine donor and a 2,4,6-triphenyl-1,3,5-triazine acceptor, shows a quantum yield of nearly 1 and a TADF lifetime as short as 0.59 µs in thin film. However, the stability of OLEDs is independent of the frontier orbital energy levels and TADF lifetime of the emitter. In contrast, the device half-life is found to decrease by five-sixths as the 0-0 energy of the singlet excitons increases by about 0.06 eV, which can be well-explained by the Arrhenius equation employing a photoreaction model. Whether in photoluminescence or electroluminescence, the contribution of long-lifetime triplet excitons to degradation is much lower than expected, which can be accounted for by how the solid-state solvation effect reduces the energy of the 3CT state and how most molecules have a low-lying locally excited triplet state.

"Fix and Click" for Assay of Sphingolipid Signaling in Single Primary Human Intestinal Epithelial Cells.

Capillary electrophoresis with fluorescence detection (CE-F) is a powerful method to measure enzyme activation in single cells. However, cellular enzymatic assays used in CE-F routinely utilize reporter substrates that possess a bulky fluorophore that may impact enzyme kinetics. To address these challenges, we describe a "fix and click" method utilizing an alkyne-terminated enzyme activation reporter, aldehyde-based fixation, and a click chemistry reaction to attach a fluorophore prior to analysis by single-cell CE-F. The "fix and click" strategy was utilized to investigate sphingolipid signaling in both immortalized cell lines and primary human colonic epithelial cells. When the sphingosine alkyne reporter was loaded into cells, this reporter was metabolized to ceramide (31.6 ± 3.3% peak area) without the production of sphingosine-1-phosphate. In contrast, when the reporter sphingosine fluorescein was introduced into cells, sphingosine fluorescein was converted to sphingosine-1-phosphate and downstream products (32.8 ± 5.7% peak area) without the formation of ceramide. Sphingolipid metabolism was measured in single cells from both differentiated and stem/proliferative human colonic epithelium using "fix and click" paired with CE-F to highlight the diversity of sphingosine metabolism in single cells from primary human colonic epithelium. This novel method will find widespread utility for the performance of single-cell enzyme assays by virtue of its ability to temporally and spatially separate cellular reactions with alkyne-terminated reporters, followed by the assay of enzyme activation at a later time and place.

Success and Safety of Needle Knife Papillotomy and Fistulotomy Based on Papillary Anatomy: A Prospective Controlled Trial.

BACKGROUND: Needle knife papillotomy (NKP) and fistulotomy (NKF) are the two most commonly used rescue techniques for patients with difficult biliary cannulation (DBC). Anatomy of the major duodenal papillae (MDP) influences the optimal precut technique for biliary access. However, comparative studies of the success and safety of NKP and NKF based on the anatomy of MDP have been scarce. METHODS: Patients with intact MDPs for therapeutic endoscopic retrograde cholangio-pancreatography (ERCP) in our center were enrolled. Early needle knife precuts were uniformly applied to patients with DBC. Difficult MDPs were classified into one of five types based on their endoscopic anatomy. Each type of MDP was allocated to NKP or NKF treatment. Patients with types 1 and 2 papillae always received NKF, 3 and 4 received NKP, and 5 could receive either. The safety and efficacy were analyzed between NKP and NKF, and among different types of MDPs. RESULTS: A total of 188 out of 1674 patients undergoing ERCP satisfied the criteria for early precutting: 75 patients were assigned to the NKP group and 113 to the NKF group. The total initial success rate of biliary cannulation (ISRBC) of the precut techniques (both NKP and NKF) for patients with DBC was 91.5%. The ISRBC of patients of the NKP group was similar to that of the NKF group (90.7% vs 92.0%, P > 0.05). The ISRBC of the patients in the swollen MDP subgroup (96.1%) was higher than that of patients in the distorted MDP subgroup (81.8%, P = 0.030). The total and specific complications of the patients of the NKP group were similar to those of the NKF group (P > 0.05). CONCLUSIONS: NKP and NKF, as selected on the basis of MDP anatomy, are equally safe and highly efficient for patients with DBC to allow biliary cannulation. Patients with swollen MDPs had a higher ISRBC than patients with distorted MDPs. Selecting a precut method based on MDP anatomy is an effective and safe strategy for patients with DBC.